Blais-Lecours 2019 Am J Respir Cell Mol Biol

Blais-Lecours P, Laouafa S, Arias-Reyes C, Santos WL, Joseph V, Burgess JK, Halayko AJ, Soliz J, Marsolais D (2019) Metabolic adaptation of airway smooth muscle cells to a SPHK2 substrate precedes cytostasis. Am J Respir Cell Mol Biol [Epub ahead of print].

» PMID: 31247144

Blais-Lecours P, Laouafa S, Arias-Reyes C, Santos WL, Joseph V, Burgess JK, Halayko AJ, Soliz J, Marsolais D (2019) Am J Respir Cell Mol Biol

Abstract: Thickening of the airway smooth muscle is central to bronchial hyperreactivity. We have shown that the sphingosine analog AAL-R can reverse pre-established airway hyperreactivity in a chronic asthma model. Since sphingosine analogs can be metabolized by sphingosine kinase 2, we investigated whether this enzyme was required for AAL-R to perturb mechanisms sustaining airway smooth muscle cell proliferation. We found that AAL-R pre-treatment reduced the capacity of live airway smooth muscle cells to use oxygen for oxidative phosphorylation and increased lactate dehydrogenase activity. We also determined that sphingosine kinase 2 was upregulated in airway smooth muscle cells bearing the proliferation marker Ki67, relative to their Ki67-negative counterpart. Comparing different stromal cell subsets of the lung, we found that high sphingosine kinase 2 levels were associated with the ability of AAL-R to inhibit metabolic activity assessed by conversion of the tetrazolium dye MTT. Knock down or pharmacologic inhibition of sphingosine kinase 2 reversed the effect of AAL-R on MTT conversion, indicating the essential role for this kinase in the metabolic perturbations induced by sphingosine analogs. Our results support the hypothesis that increased sphingosine kinase 2 levels in proliferating airway smooth muscle cells could be exploited to counteract airway smooth muscle thickening with synthetic substrates. • Keywords: AAL-R, Asthma, FTY720, Metabolism, Sphingolipids • Bioblast editor: Plangger M • O2k-Network Lab: CA Quebec Soliz J

Labels: MiParea: Respiration, Genetic knockout;overexpression, Pharmacology;toxicology  Pathology: Other 

Organism: Human  Tissue;cell: Other cell lines  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, OXPHOS, ET  Pathway: ROX  HRR: Oxygraph-2k 

Labels, 2019-07